Abstract Cardiovascular disease (CVD) is the leading cause of death in the US and globally. In the US, the estimated direct and indirect costs of CVD exceed half a trillion dollars each year. These burdens may increase further with the aging of the population, escalating healthcare costs, improved patient survival following cardiac events, and increasing rates of major CVD risk factors such as obesity and diabetes. Our own work and that of many others has demonstrated that poor dietary habits are a major preventable cause of CVD. Our prior work has shown that excess salt and trans fats and insufficient polyunsaturated fats (in place of saturated fats), fruits and vegetables, and seafood omega-3 fats each account for tens of thousands of CVD deaths in the US each year. High intakes of sugar-sweetened beverages (SSBs) and processed meats and inadequate intake of nuts and whole grains also contribute to CVD risk. Clearly, achieving dietary change to improve CVD is a major challenge that needs to be addressed. Considering that most CVD is premature and can be prevented or delayed, the trillion-dollar question is which interventions are most effective to improve diet and reduce CVD? We propose to evaluate the comparative-effectiveness of evidence-based population interventions to improve diet (Aim 1). We will focus on population-level approaches as these are more sustainable and less costly compared to individual-level ones. We will select the most promising population interventions based on the results of our preliminary work, and quantify their effect sizes on diet based on pooling the published evidence. We will primarily focus on effect sizes for fruits and vegetables, dietary fats, salt, an SSBs. Depending on data availability, we will secondarily consider seafood omega-3 fats, nuts, whole grains, and processed meats. We will use the results of Aim 1 to subsequently evaluate the comparative-effectiveness of evidence-based population dietary interventions to reduce CVD mortality in the US by age and sex, using nationally-representative data (Aim 2). There is clearly an urgent need to develop a consistent methodology to compare the impact of different population interventions on CVD in the US context. As part of this effort, we will develop and extend from our prior work three different models. The assessment of the comparative-effectiveness of evidence-based population strategies to improve diet and reduce CVD, and the development of a consistent methodology to perform such an assessment, are each novel, and will provide essential insights for evidence-based preventive efforts in the US, and also identify important gaps for future studies. Application of that knowledge will be imperative in extending healthy life and reducing enormous and ever-increasing burdens of CVD in the US.